Comment: A really interesting approach to thinking about HIV and drug overdose mortality, through the lens of syndemics – a hot topic in public health – and risk environments. With the bonus of an important review of data from several Central Asian states.

Comments: More excellent work from this team. I particularly appreciate the estimate of the reduction in overdose risk with age. In a mathematical model of overdose, we estimated a 50% reduction in the risk of overdose over 10 years of use, whereas this paper suggests the figure is closer to 20% - data that will be very helpful in future iterations.

Comments: An intriguing look at electronic record “triggers” to identify adverse events. Administration of naloxone had a positive-predictive value of 91% for opioid overmedication. This is a secondary care setting, not an emergency setting. In an emergency or field setting, such a trigger may still have a high positive predictive value, but the negative predictive value is likely inadequate to justify its use for out-of-hospital overdose detection.

Comment: Almost half of the deaths among ex-prisoners in Australia from 2000-2007 were due to drug overdose, 82% of which demonstrated heroin and/or morphine on toxicology. Those who died of drug-related death were less likely that those who died of other causes to have mental health conditions or a history of self-harm. The were more likely to have a history of heroin use, drug withdrawal, injecting drugs, and drug overdose.

Comment: The authors interviewed next of kin or best contacts, a very compelling approach to studying the characteristics of opioid analgesic use resulting in overdose death. About a quarter had a history of heroin use and the vast majority had been to the emergency department previously for problems related to substance use. Over 90% had gotten prescription pain medication from a healthcare provider within the year leading up to their death (prescription database studies have suggested one to two-thirds of deaths are due to drugs prescribed to the decedent, but getting some prescriptions from a healthcare provider does not necessarily mean they received the agent that led to the overdose from a provider).

Comment: This is an intriguing analysis of the complex issue of suicide and drug overdose based on a large cross-sectional dataset of substance use treatment patients (N=5892). Twenty percent were in treatment for marijuana, 42% for alcohol, 61% for cocaine, and 19% for heroin. I would be interested in seeing the analysis restricted to those in treatment for heroin, as that is a more homogenous group at higher risk for overdose. Also, while we know that only a small proportion of heroin overdose among heroin users is intentional, an analysis such as this may help to tease apart how much overdose is related to attempts at self-harm.

Comment: Some potential interactions of the HCV protease inhibitor with selected opioids. Hopefully we won’t be using telaprevir too much longer as more advanced, effective, and easily tolerated regimens are expected as early as the end of 2013.

Comments: For patients on any opioid medications, benzodiazepines are associated with an increased risk of overdose. This study of 328 buprenorphine maintenance patients didn’t find an association with benzodiazepine prescriptions and overdose, but did find an association with more frequent emergency department visits and injury-related ED visits. We may never learn if benzodiazepines are causal in this pathway or merely a marker, but these data do contribute to the overall concern.

Comments: Interesting analysis of a relatively new dataset including cases evaluated by medical toxicologists from multiple sites. Opioids were a leading issue (although this is a set of referred cases and opioid overdose rarely requires referral, so the contribution of opioids to overdose events should be very much underestimated in this cohort).

Comment: Interesting paper exploring the persistent impairment in cognitive functioning after drug poisoning. The authors focused on possible residual drug effect, although I do wonder if there is a cognitive impact of non-fatal overdose beyond residual drug effect.

Comment: High-dose opioids can cause QT prolongation, a hypothetical bugaboo for methadone maintenance. What is QT prolongation? It is a warning sign that somebody might be at risk for a potentially fatal heart rhythm. More detail, you ask? Well, the EKG is a record of electrical activity in the heart – see below. Some medications make the time from Q to T longer. If it gets long enough (usually requiring very high doses of opioids in combination with either other medications or a genetic tendency to have a long QT) it can result in a dangerous heart rhythm.

Comments: Survey of prescription opioid use among treatment program patients. Use for reasons other than pain relief was associated with overdose as well as use of several other agents that increase the risk of overdose.

Comments: An analysis from the fentanyl-laced heroin overdose fatality epidemic that struck the eastern United States from 2005-2007. This epidemic was substantial and deserves mention in any modern history of overdose in North America as it led to the active engagement of several federal agencies in addressing overdose.

Comments: Nice analysis of WONDER data on opioid overdose death, comparing heroin to prescription opioids. As we know, the current epidemic is opioid analgesics, although there has been a more recent increase in heroin deaths – likely due to the transition that often occurs from opioid analgesics to heroin.

Comment: I particularly appreciate the authors’ effort to put some numbers behind opioid analgesic overdose. Based on two prior papers, they state that the rate of overdose among high-dose opioid analgesic users is 1.8% and that 12% of overdoses are fatal, suggesting a death rate of 2 per 1,000 person years of high-dose opioid prescription. I would love to see other analyses with consistent results, but this is certainly a place to start. To put this in context, among heroin users, around 20% overdose in a given year and around 5% of overdoses are fatal.

Comment: Methadone was responsible for about a third of opioid analgesic deaths in 2010. It is important to note that these deaths are mostly from pain prescriptions rather than maintenance programs. In addition, it is important to consider that the causal agents in opioid analgesic deaths vary by state, along with prescribing patterns. For example, this analysis of 13 states did not include Florida, which had an enormous problem with oxycodone/OxyContin prescribing. In fact, a major driver in the transition to methadone for many state insurance programs was the growing OxyContin overdose death epidemic. Nonetheless, there are complexities to titrating methadone that are poorly understood by many providers and most patients

Comment: Very challenging and intriguing case-control study (300 cases) of prescription overdose death from the CDC injury center. This is a boost in our understanding of the risk factors for overdose death, which include dose of opioids (a surprisingly steep increase in risk with relatively low doses of opioids [as low as 20 morphine equivalents daily]) and number of prescriptions (overlapping prescriptions for opioids appeared to be a major issue). The finding that selected opioids were associated with death is intriguing and worthy of further exploration. The strong association with buprenorphine prescription (although with a very wide confidence interval) is discussed by the authors with a reasonable conclusion that this may be related to resumption of heroin use rather than overdose on buprenorphine itself. The fact that the association with methadone is similar to that with fentanyl and hydromorphone (Dilaudid) suggests that overdose risk may reflect as much the population receiving the prescription as the pharmacology of a given agent.

Hall MT, Leukefeld CG, Havens JR.Am J Drug Alcohol Abuse. 2013 Jul;39(4):241-6. doi:Comment: I can’t access this article, but have some concerns about the utility of the analysis of covariates presented in the abstract.

Comments: An adaptation of the model developed for the United States, taking into account structural differences, epidemiologic data, and costs in Russia. Because of limitations in emergency medical services in Russia, the high rate at which overdoses are witnessed, and the very low costs of naloxone, this intervention is likely to be even more cost-effective in Russia than it appears to be in the United States.

Comment: Unable to access. Interviews with 21 drug injectors and 21 pharmacy staff. Overall there was good acceptance of the concept, although some misinformation about naloxone, some concerns about drug user and pharmacy staff interactions, and some concerns about cost.

Comments: A qualitative look at providers feelings about providing naloxone to “drug users” and, separately, to “pain patients.” This is a great and useful analysis – and honestly surprisingly positive across the board. The major concern raised seemed to be that naloxone not be the only thing done to try to reduce overdose. This is a pretty dramatic shift in attitudes since earlier evaluations of provider opinion on lay naloxone (Beletsky et al 2007, Coffin et al 2003).

Comments: This is an intriguing report. Early use of naloxone (by paramedics in this case) may result in less need for intubation, even if patients continue to experience respiratory distress. This suggests that faster administration of pre-hospital naloxone may reduce the need for invasive interventions.

Comment: We are in desperate need of standardized and validated measures for overdose and naloxone distribution. These scales may be useful, although as a word of caution several elements are specific to UK programming.

Comments: A long-awaited paper for which the authors deserve high praise, as they have produced the first real evidence of naloxone effectiveness and arguably the most important contribution to naloxone literature to-date. Although not randomized, the interrupted time series analysis is respectable and the results are impressive.

Comments: I’ve wanted to write this paper for about a decade, when I thought about cost-effectiveness as three to four calculations on the back of a napkin, rather than years of work and RAM-straining matrices. There’s a long way to go with overdose research that will certainly contribute to future iterations of the model. In the meantime, this is probably a fair, if quite conservative, initial estimate. There is one sensitivity analysis – in which naloxone results in behavior change such that overdose risk is lower – which I suspect may be closer to the actual truth.

Comment: A descriptive piece on the application of the Massachusetts overdose education and naloxone distribution project to methadone maintenance programs. Massachusetts has been a leader in broad-based naloxone distribution and innovative efforts to evaluate the intervention.

Comment: Naloxone administration by the intranasal route has been increasingly adopted by emergency medical service programs, at least around the United States. However, this route of administration has never been approved by the Food and Drug Administration (this is not unusual or illegal – medical providers frequently use medications “off-label” for indications or by routes that have not gone through the expensive process of FDA approval). This is a nice evaluation of how quickly a drug can be administered by intranasal (87 seconds) compared to IV (178 seconds) and the perceived safety of those two routes of administration. Advanced paramedic trainees preferred the intranasal route.

Comment: This analysis failed to consider heroin overdose prevention programming – i.e. naloxone distribution – that was scaled up over the exact same period that buprenorphine treatment expanded and heroin overdoses declined. While not all variables can be considered in the interrupted time series approach, not considering the impact of a naloxone-based “overdose prevention program” seems to be a major flaw in the presentation. Disappointing that this was not rigorously addressed.

Comment: A discussion including the benefits of supervised injection facilities in reducing overdose deaths, sharing of injection equipment, public drug use, and utilization of emergency medical services.

Comment: This was a randomized, placebo-controlled trial comparing naltrexone implant to oral naltrexone to nothing for preventing relapse to opioid dependence among detoxified patients in Russia. Participants were followed for six months and then followed up a year later to see if there was more death from overdose. The implant was more effective in retaining participants through the six months although by 3 months off therapy there was no difference between the groups. Authors only report “no evidence of increased risk of death due to overdose after naltrexone treatment” and cite the initial paper showing injectable naltrexone as effective for opioid dependence in Russia (I’m unclear as to why this citation was present). I find this radically insufficient. Naltrexone has lab evidence (animal evidence shows that exposing opioid receptors to naltrexone makes them more sensitive to opioids than mere abstinence) and clinical evidence (high death rates after oral naltrexone treatment) suggesting that it increases risk of overdose and overdose death. The authors of this paper provide no details as to how they showed no evidence of increased overdose. How many people were they able to follow-up with at 18 months (their numbers were really small to begin with)? Did they inquire as to non-fatal overdose? How did they collect information about overdose death (coroners in Russia rarely identify overdose as a cause of death due to stigma and payment issues)? While extended-release naltrexone formulations *might* have less of an association with overdose, the concerns about oral naltrexone are well-established - how did the investigators get approval for oral naltrexone for opioid users from a U.S. government funded study? This is a vulnerable population for whom greater attention to toxicities should be demanded. A high level of attention to overdose outcomes might put to rest these concerns, but I have not seen that as of yet.

Comment: Avoiding overdose is a significant concern for staff at heroin treatment programs. As those who had used benzodiazepines or cocaine have been more likely to overdose in the program, nurses have managed this concern in part by assessing the level of intoxication prior to providing heroin.

1 comment:

Excellent summary; love the commentaries.Btw, has there been a good systematic review of literature about opioid overdose since the classic: Darke, S. and D. Zador (1996). "Fatal heroin 'overdose': a review." Addiction 91(12): 1765-1772? I'm most interested in the literature about location of ODs.